CN103172603B - High-selectivity lovastatin extraction method by esterifying lovastatin acid - Google Patents
High-selectivity lovastatin extraction method by esterifying lovastatin acid Download PDFInfo
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- CN103172603B CN103172603B CN201110436127.4A CN201110436127A CN103172603B CN 103172603 B CN103172603 B CN 103172603B CN 201110436127 A CN201110436127 A CN 201110436127A CN 103172603 B CN103172603 B CN 103172603B
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- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 title claims abstract description 61
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 title claims abstract description 48
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 title claims abstract description 48
- 229960004844 lovastatin Drugs 0.000 title claims abstract description 47
- QLJODMDSTUBWDW-BXMDZJJMSA-N mevinolinic acid Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C=C21 QLJODMDSTUBWDW-BXMDZJJMSA-N 0.000 title claims abstract description 14
- 238000000605 extraction Methods 0.000 title abstract description 3
- 239000002253 acid Substances 0.000 claims abstract description 24
- 239000012043 crude product Substances 0.000 claims abstract description 19
- 239000012074 organic phase Substances 0.000 claims abstract description 17
- 238000005406 washing Methods 0.000 claims abstract description 14
- 239000000047 product Substances 0.000 claims abstract description 13
- 239000007788 liquid Substances 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 229910017053 inorganic salt Inorganic materials 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 43
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 23
- 238000005886 esterification reaction Methods 0.000 claims description 23
- 230000032050 esterification Effects 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- XUPYJHCZDLZNFP-UHFFFAOYSA-N butyl butanoate Chemical compound CCCCOC(=O)CCC XUPYJHCZDLZNFP-UHFFFAOYSA-N 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- 238000005516 engineering process Methods 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 4
- 229940043232 butyl acetate Drugs 0.000 claims description 4
- NMJJFJNHVMGPGM-UHFFFAOYSA-N butyl formate Chemical compound CCCCOC=O NMJJFJNHVMGPGM-UHFFFAOYSA-N 0.000 claims description 4
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 claims description 2
- UHOPWFKONJYLCF-UHFFFAOYSA-N 2-(2-sulfanylethyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCS)C(=O)C2=C1 UHOPWFKONJYLCF-UHFFFAOYSA-N 0.000 claims description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 2
- JGFBQFKZKSSODQ-UHFFFAOYSA-N Isothiocyanatocyclopropane Chemical compound S=C=NC1CC1 JGFBQFKZKSSODQ-UHFFFAOYSA-N 0.000 claims description 2
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 claims description 2
- PWLNAUNEAKQYLH-UHFFFAOYSA-N butyric acid octyl ester Natural products CCCCCCCCOC(=O)CCC PWLNAUNEAKQYLH-UHFFFAOYSA-N 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- 229940017219 methyl propionate Drugs 0.000 claims description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 2
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 229940090181 propyl acetate Drugs 0.000 claims description 2
- 238000005201 scrubbing Methods 0.000 claims description 2
- 238000000638 solvent extraction Methods 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019798 tripotassium phosphate Nutrition 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 10
- 238000007273 lactonization reaction Methods 0.000 abstract description 8
- GZGUDHDMNATZDU-CRMSOXFQSA-N [(4r)-2-[2-[(1s,2s,6r,8s,8ar)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]ethyl]-6-oxooxan-4-yl] (3r,5r)-7-[(1s,2s,6r,8s,8ar)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]-3,5-dihydrox Chemical compound C([C@@H]1C)=CC2=C[C@H](C)C[C@H](OC(=O)[C@@H](C)CC)[C@@H]2[C@H]1CCC(OC(=O)C1)C[C@H]1OC(=O)C[C@H](O)C[C@H](O)CC[C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@H](OC(=O)[C@@H](C)CC)[C@H]12 GZGUDHDMNATZDU-CRMSOXFQSA-N 0.000 abstract description 5
- 238000007689 inspection Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000000855 fermentation Methods 0.000 abstract description 2
- 230000004151 fermentation Effects 0.000 abstract description 2
- 238000001914 filtration Methods 0.000 abstract description 2
- 230000002378 acidificating effect Effects 0.000 abstract 1
- 230000005855 radiation Effects 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 9
- 150000002596 lactones Chemical class 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000000539 dimer Substances 0.000 description 6
- 239000003377 acid catalyst Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 108010007622 LDL Lipoproteins Proteins 0.000 description 3
- 102000007330 LDL Lipoproteins Human genes 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- 241000228212 Aspergillus Species 0.000 description 2
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 2
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 239000012296 anti-solvent Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 239000002361 compost Substances 0.000 description 2
- 238000006471 dimerization reaction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 2
- -1 hydrocarbons compound Chemical class 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 0 *C(C[C@@](C1)O)OC1=O Chemical compound *C(C[C@@](C1)O)OC1=O 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 240000004859 Gamochaeta purpurea Species 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- 108010062497 VLDL Lipoproteins Proteins 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229940099246 mevacor Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- JQRYUMGHOUYJFW-UHFFFAOYSA-N pyridine;trihydrobromide Chemical compound [Br-].[Br-].[Br-].C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1 JQRYUMGHOUYJFW-UHFFFAOYSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003930 superacid Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Abstract
The invention discloses a high-selectivity lovastatin extraction method by esterifying lovastatin acid, which comprises the following steps: regulating the pH value of a lovastatin production fermentation liquid to an acidic state, filtering, extracting the filter residue with an organic solvent, and taking an organic phase; sequentially washing the organic phase with a weakly alkaline inorganic salt water solution and dilute acid; carrying out microwave treatment on the organic phase in high vacuum at low temperature, wherein the energy radiation of the electromagnetic waves can lactonize the open-ring acid of lovastatin and increase kinetic energy of water, and the removal of the lovastatin acid can implement specificity and high yield of lactonization; concentrating the organic phase, and crystallizing to obtain the lovastatin crude product; and finally, decolorizing and recrystallizing the crude product to obtain the lovastatin product. The inspection indicates that no open-ring acid is detected in the lovastatin crude product, and the lovastatin dimer content is lower than 0.07%.
Description
Technical field
The present invention relates to the process for purification of lovastatin, what be specifically related to produce from compost aspergillus is rich in the fermented liquid of lovastatin and extracts lovastatin, and carries out microwave-assisted and to lactonize the method for purification of process.
Background technology
Lovastatin (LOVASTATIN), chemical name is: (S)-2-Methyl Butyric Acid-(1S, 3S, 7S, 8S, 8aR)-1,2,3,7,8,8a-six hydrogen-3,7-dimethyl-8-{2-[(2R, 4R)-4-hydroxyl-6 oxo-2-THP trtrahydropyranyl]-ethyl }-1-naphthalene ester; Molecular formula is C
24h
36o
5, molecular weight 404.55, structure is as follows:
1987, the blood lipid-lowering medicine Lip river of Merck & Co., Inc. was cut down him and is ordered after (lovastatin, Mevacor) obtain FDA approval listing, and cause the concern of medical circle immediately, the new stage of blood lipid-lowering medicine has been started in the success of this medicine.This medicine is by suppressing the activity of the rate-limiting enzyme HMG-CoA reductase (HMG-CoA reductase) in cholesterol biosynthesis process, reduce the synthesis of liver cholesterol, low-density lipoprotein (LDL) acceptor is stimulated to produce, and strengthen the removing of low-density lipoprotein in blood plasma, Very Low Density Lipoprotein also reduces, and is the HMG-CoA reductase inhibitor of first, whole world approval listing.
From the lovastatin that the fermentation of compost aspergillus produces, be present in fermented liquid with the form of lactone and acid, wherein only have the lovastatin of lactone form just to have commercial application value, the lovastatin of sour form is converted into lactone form by a kind of process lactonized that is called.The process of lactonizing is a balanced reaction, is converted into the lactone of closed loop by the dihydroxylated acid form of open loop, as follows:
Being an equilibrium process because lactonize, in order to improve the productive rate of product, must adopting certain methods that balance is moved to lactone direction.In addition, lactonizing is intramolecular esterification, often with intermolecular esterification in esterification process, causes the generation of the impurity such as dimer or more much higher aggressiveness.
The formation of dimer impurity makes esterification complicated, reduces the quality of final product simultaneously.Dimer impurity is just difficult to removing once formation, and it often accounts for 0.08% ~ 0.4% of product.Formed to make dimer and minimize, in lactonization reaction, often improve extent of dilution, its cost is that production efficiency is low, and this is disadvantageous to commercial scale production.
Free acid or its salt normally at high temperature reflux with inert solvent by the Lactonization method of existing bibliographical information, or use strong acid catalyst lactonization reaction at normal temperatures.The disclosed method of US4820850 (A) is: heating free acid or its salt, such as ammonium salt in high-boiling hydrocarbons compound solvent (as toluene), be heated to reflux temperature (usual 100 to 110 DEG C) 7-8 hour.At these elevated temperatures, intramolecular esterification reaction is principal reaction.In addition, the water component distillation formed as byproduct of reaction is constantly removed, and reaction can be made close to complete (namely balance and move to the direction that lactonizes).Lactonize in process under heated reflux condition, due to intermolecular esterification, generate the generation of dimerization lovastatin, can reduce final in the quality of ester products.
US4916239 (A) discloses the method for at room temperature carrying out esterification: under strong acid catalyst exists, the free ammonium salt of process in the mixture of acetic acid and water.After free ammonium and acid balance are set up (reaction proceeds to the transformation efficiency of 50%), add water gradually, its consumption is enough to lactone to crystallize out from reaction medium.Ester products in separating out from solution, is conducive to the carrying out lactonized.The shortcoming of the method is that inconvenience uses strong acid catalyst in extensive synthesis.The consumption of strong acid catalyst (such as: formic acid, phosphoric acid, trifluoroacetic acid, sulfuric acid, hydrochloric acid, p-methyl benzenesulfonic acid, methylsulfonic acid) changes through being everlasting between 1.2 to 1.5 molar equivalents, be difficult to operation and the process problem causing environment not accept, especially commercial scale production environmental problem, can not be ignored.In addition, the method also has the following disadvantages: the super acid catalyst used needs to neutralize with alkali; Esterification only completes about 60% after equilibration had been achieved; Too fast or add water prematurely and all can cause serious precipitation problem, cause filtering very difficult; Reaction and work for the treatment of subsequently need just can complete, because this reducing the efficiency of method for about 9-12 hour.
US5917058 (A) discloses a kind of without the Lactonization method under severe corrosive acid and violent heating condition.The method comprises: in the water-less environment of inertia, use acetic acid treatment open loop hydrochlorate under room temperature or mild temperature, preferably its ammonium salts.Acetic acid is solvent and catalyzer.The process that lactonizes does not add strong acid catalyst.By adding anti-solvent by the product Crystallization Separation that lactonizes out after reaction terminates.Disclosed anti-solvent is water, hexane, heptane or hexanaphthene.Be a balanced reaction because lactonize, byproduct of reaction is water, must be removed, and balance is moved to esterification direction.Use acetic acid in the method, cause generating ammonium acetate, ammonium acetate can absorb another by product---water.It is reported that the method productive rate can reach 85-95%, and purity reaches 95-98%.
US5939564 (A) also discloses a kind of Lactonization method without severe corrosive acid.In organic solvent under anhydrous condition, the ring-opened hydroxy of salt form is heated to the temperature of solvent refluxing from room temperature 20 DEG C.This mixture is using gentle catalyst treatment from room temperature subsequently at the temperature of 50 DEG C.The catalyzer of described gentleness is organic bases and inorganic or organic acid salt, such as pyridinium tribromide hydrochlorate, pyridine hydrochloride or piperidines tosilate.Then add elutriation to go out to lactonize product, from mixture, finally collect the product of precipitation.The method can obtain at most the lovastatin of 98.7% purity.
Aforesaid method all can cause the dimeric obvious generation of lovastatin.In addition, in the process from lovastatin synthesis Simvastatin, in the process of lactonizing, dimer impurity is also had to be formed.Therefore, a kind of purification process that can reduce dimer impurity level is needed.
Summary of the invention
The object of this invention is to provide the Lactonization method in a kind of lovastatin leaching process, in existing lovastatin extraction process, on the basis obtaining lovastatin and lovastatin open loop acid mixture, under the middle and high vacuum of high boiling solvent, under lesser temps, electromagnetic microwave is utilized to provide energy to carry out pass ring lactonization reaction, avoid the generation of dimerization lovastatin, improve the selectivity of esterification.
Technical scheme of the present invention is as follows:
A lovastatin extracting method for highly selective esterification treatment lovastatin acid, comprises the steps:
1) the fermented liquid acid of producing lovastatin is adjusted to acidity (pH=1 ~ 6), filter and abandon filtrate, filter residue organic solvent extraction, gets organic phase;
2) by step 1) after the solution washing of gained organic phase with weakly alkaline inorganic salt, then dilute acid wash;
3) under the vacuum condition of air pressure≤0.01MPa, at-25 DEG C ~ 35 DEG C temperature, to step 2) washing after organic phase carry out microwave treatment;
4) by the sample concentration after microwave treatment, crystallization, lovastatin crude product is obtained;
5) carry out desolventing technology to lovastatin crude product, then recrystallization, isolation of crystalline is also dry, obtains lovastatin product.
Above-mentioned steps 1) can use in hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and oxalic acid one or more regulate pH to 1 ~ 6 of fermented liquids, preferably use hydrochloric acid; The organic solvent extracted filter residue can be lower member ester or lower alcohol, such as, in butyl butyrate, ethyl acetate, ethyl formate, methyl acetate, propyl acetate, propyl formate, methyl propionate, ethyl propionate, propyl propionate, butyl formate, methyl-butyrate, butylacetate, ethyl butyrate, methyl alcohol, ethanol, Virahol and butanols one or more, preferred butyl butyrate.
Step 2) organic phase first uses the solution washing of the weakly alkaline inorganic salt such as sodium bicarbonate, tertiary sodium phosphate, saleratus or Tripotassium phosphate, preferably with 1% ~ 6% sodium hydrogen carbonate solution washing; Then use the weak acid scrubbings such as the dilute hydrochloric acid of 0.2N ~ 3N, dilute sulphuric acid or dilute phosphoric acid, preferably with the washing of 0.2N ~ 3N dilute hydrochloric acid, wash temperature at 0 DEG C within the scope of 35 DEG C.
Step 3) microwave treatment by electromagnetic energy emission, make open loop acid lactone, treatment time complies with the microwave power of handled sample size and use and determines, and those skilled in the art, for the sample of required process, can obtain suitable treatment condition by the experiment of limited number of time.Such as, for from 12L fermented liquid through step 1) and 2) the 1200mL sample that obtains, 300W microwave treatment 40-100min.
Step 5) desolventing technology be generally first lovastatin crude product is dissolved in organic solvent, then decolour with gac.Here can the lower alcohol such as organic solvent such as methyl alcohol, ethanol, Virahol, butanols, or the lower member ester such as ethyl acetate, butylacetate, or the lower ketones such as acetone, butanone, preferred alcohol.
The present invention is in the leaching process of lovastatin, at a lower temperature, utilize and provide energy apply in esterification microwave fixed point, by electromagnetic energy emission, make open loop acid lactone, and increase the kinetic energy of water, be easy to separate from solvent, taken away by vacuum, the specificity and the high yield that realize esterification are forthright.To step 4) inspection of gained crude product, do not find open loop acid, lovastatin dimer content is lower than 0.07%.
Embodiment
Below by embodiment, the present invention is described in further detail, but this is not limitation of the present invention, those skilled in the art, according to basic thought of the present invention, can make various amendment or improvement, only otherwise depart from basic thought of the present invention, all within the scope of the present invention.
Embodiment 1
12L fermented liquid is cooled to 16 DEG C, is adjusted to pH2.8 with 3N hydrochloric acid, filter, filter residue adds butyl butyrate 900ml, 400ml extracting twice respectively, merges organic phase; Organic phase is first washed with 5% sodium hydrogen carbonate solution 300ml, then with 1N hydrochloric acid 300ml washing at 16 DEG C; Open vacuum and reach-0.098MPa (namely air pressure is 0.002MPa), keep 16 DEG C of 45min, then open 300W microwave device, after 65min, close microwave; Be warming up to 80 DEG C, be concentrated to 200ml, be progressively cooled to 10 DEG C of crystallizations; Obtain crude product after centrifugal drying, crude product inspection does not find open loop acid, and lovastatin dimer content is lower than 0.07%; Crude product is dissolved in activated carbon decolorizing after ethanol, recrystallization of then lowering the temperature, centrifugal, washing, dry product.
Embodiment 2
12L fermented liquid is cooled to 26 DEG C, is adjusted to pH2.9 with 3N hydrochloric acid, filter, filter residue adds butyl butyrate 900ml, 400ml extracting twice respectively, merges organic phase; Organic phase is first washed with 5% sodium hydrogen carbonate solution 300ml, then with 1N hydrochloric acid 300ml washing at 26 DEG C; Open vacuum and reach-0.098MPa (namely air pressure is 0.002MPa), keep 26 DEG C of 45min, then open 300W microwave device, after 65min, close microwave; Be warming up to 85 DEG C, be concentrated to 200ml, be progressively cooled to 10 DEG C of crystallizations; Obtain crude product after centrifugal drying, crude product inspection does not find open loop acid, and lovastatin dimer content is lower than 0.07%; Crude product is dissolved in activated carbon decolorizing after ethanol, recrystallization of then lowering the temperature, centrifugal, washing, dry product.
Embodiment 3
12L fermented liquid is cooled to 10 DEG C, is adjusted to pH2.8 with 3N hydrochloric acid, filter, filter residue adds butyl butyrate 900ml, 400ml extracting twice respectively, merges organic phase; Organic phase is first washed with 5% sodium hydrogen carbonate solution 300ml, then with 1N hydrochloric acid 300ml washing at 10 DEG C; Open vacuum and reach-0.099MPa (namely air pressure is 0.001MPa), keep 10 DEG C of 60min, then open 300W microwave device, after 95min, close microwave; Be warming up to 70 DEG C, be concentrated to 200ml, be progressively cooled to 10 DEG C of crystallizations; Obtain crude product after centrifugal drying, crude product inspection does not find open loop acid, and lovastatin dimer content is lower than 0.07%; Crude product is dissolved in activated carbon decolorizing after ethanol, recrystallization of then lowering the temperature, centrifugal, washing, dry product.
Claims (9)
1. a lovastatin extracting method for highly selective esterification treatment lovastatin acid, comprises the following steps:
1) the fermented liquid acid of producing lovastatin is adjusted to acidity, filter and abandon filtrate, filter residue organic solvent extraction, gets organic phase;
2) by step 1) after the solution washing of gained organic phase with weakly alkaline inorganic salt, then dilute acid wash;
3) under the vacuum condition of air pressure≤0.01MPa, at-25 DEG C ~ 35 DEG C temperature, to step 2) washing after organic phase carry out microwave treatment;
4) by the sample concentration after microwave treatment, crystallization, lovastatin crude product is obtained;
5) carry out desolventing technology to lovastatin crude product, then recrystallization, isolation of crystalline is also dry, obtains lovastatin product.
2. the lovastatin extracting method of highly selective esterification treatment lovastatin acid as claimed in claim 1, it is characterized in that, step 1) one or more in middle hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and oxalic acid regulate pH to 1 ~ 6 of fermented liquids, then filter.
3. the lovastatin extracting method of highly selective esterification treatment lovastatin acid as claimed in claim 1, it is characterized in that, step 1) in organic solvent that filter residue is extracted be selected from butyl butyrate, ethyl acetate, ethyl formate, methyl acetate, propyl acetate, propyl formate, methyl propionate, ethyl propionate, propyl propionate, butyl formate, methyl-butyrate, butylacetate, ethyl butyrate, methyl alcohol, ethanol, Virahol and butanols one or more.
4. the lovastatin extracting method of highly selective esterification treatment lovastatin acid as claimed in claim 1, is characterized in that, step 2) described in weakly alkaline inorganic salt be sodium bicarbonate, tertiary sodium phosphate, saleratus or Tripotassium phosphate.
5. the lovastatin extracting method of highly selective esterification treatment lovastatin acid as claimed in claim 1, is characterized in that, step 2) described in diluted acid be the dilute hydrochloric acid of 0.2N ~ 3N, dilute sulphuric acid or dilute phosphoric acid.
6. the lovastatin extracting method of highly selective esterification treatment lovastatin acid as claimed in claim 1, is characterized in that, step 2) temperature of weak acid scrubbing at 0 DEG C within the scope of 35 DEG C.
7. the lovastatin extracting method of highly selective esterification treatment lovastatin acid as claimed in claim 1, is characterized in that, in step 3) for the sample of 1200mL, 300W microwave treatment 40-100min.
8. the lovastatin extracting method of highly selective esterification treatment lovastatin acid as claimed in claim 1, is characterized in that, step 5) lovastatin crude product is dissolved in organic solvent, then carry out desolventing technology with gac.
9. the lovastatin extracting method of highly selective esterification treatment lovastatin acid as claimed in claim 8, is characterized in that, step 5) organic solvent used is methyl alcohol, ethanol, Virahol, butanols, ethyl acetate, butylacetate, acetone or butanone.
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| CN1406938A (en) * | 2001-08-27 | 2003-04-02 | 第一制糖株式会社 | Lactonization in course of preparing lovastatin or similarities |
| CN1583736A (en) * | 2004-06-03 | 2005-02-23 | 山东鲁抗医药股份有限公司 | Extraction and refinement of lovastatin |
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| CN1406938A (en) * | 2001-08-27 | 2003-04-02 | 第一制糖株式会社 | Lactonization in course of preparing lovastatin or similarities |
| CN1583736A (en) * | 2004-06-03 | 2005-02-23 | 山东鲁抗医药股份有限公司 | Extraction and refinement of lovastatin |
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